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27 April 2018

Residual cardiovascular risk: refocus on a multifactorial approach

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Guidelines focus on reducing low-density lipoprotein cholesterol (LDL-C), given indisputable evidence that this is a key driver of both clinical and subclinical atherosclerotic cardiovascular disease (ASCVD).1-3) Yet it is also recognized that even with optimal LDL-C lowering therapy, a high residual cardiovascular risk persists.4 Estimates of the magnitude of this residual cardiovascular risk are mainly derived by clinical trial databases. However, given that clinical trials tend to enrol a homogeneous patient population, it is unclear whether findings from trials regarding the residual cardiovascular risk on lipid-lowering therapy (LLT) are relevant to the general population.

This month’s Focus aimed to address this gap in evidence by quantifying absolute and relative residual cardiovascular risk in an unselected cohort of individuals on long-term LLT in the general population.5 Given its relevance to risk estimation and decision making about medication, absolute risk may a better measure for quantifying residual risk in this sample.6 The study showed that, irrespective of LDL-C levels, individuals on LLT had about a 3-fold increase in absolute risk of incident cardiovascular events compared with those with LDL-C levels <100 mg/dl and not on LLT.

It is important to bear in mind that the modifiable component of residual cardiovascular risk is the culmination of modifiable risk factors that are inappropriately addressed by current management approaches. While it was proposed that at least part of this residual risk was attributable to a worse profile of other cardiovascular risk factors, after adjustment those individuals on LLT who attained LDL-C levels <130 mg/dl still had about 50% higher risk of incident ASCVD events. Furthermore, while individuals on LLT and with higher LDL-C levels had more subclinical ASCVD, adjustment for this only modestly attenuated residual cardiovascular risk estimates. Adjustment for other potential residual risk factors, including inflammatory biomarkers, also did not attenuate this risk.5

This study underlines that while LDL-C is undoubtedly an important driver of ASCVD, residual cardiovascular risk persists. Recent studies have indicated that strategies aimed at further lowering of LDL-C, below current goals recommended by guidelines,7 as well as targeting inflammation,8 may decrease this risk. However, it is also clear that other contributors to this risk – both lipid and non-lipid-related – are involved. Indeed, it should be borne in mind that cholesterol is also carried on triglyceride-rich lipoproteins and their remnants, and that higher levels of these lipid parameters are also associated with increased cardiovascular risk.9 Ongoing studies are evaluating whether targeting these factors will impact this risk. This month’s Landmark study describes the EVAPORATE study, which will evaluate the effects of icosapent ethyl, a pure prescription eicosapentaenoic acid ethyl ester, on atherosclerotic plaque as an adjunct to statin therapy.(10) This imaging study will provide important mechanistic insights for the cardiovascular outcomes study Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial (REDUCE-IT), anticipated later this year.11 Additionally, improved understanding of the biology and genetics of triglyceride-rich lipoprotein metabolism has suggested new targets, including angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III.12

This is clearly an exciting time for lipid research, especially with the resurgence of thinking about the relevance of triglyceride-rich lipoproteins and their remnants to lipid-related residual cardiovascular risk. Will targeting these lipid measures offer at least part of the key to reducing this risk? We hope to have some answers before too long….

1. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;253:281-344.
2. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-2381.
3. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.
4. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol. 2014 Jan 24;13:26.
5. Lieb W, Enserro DM, Larson MG et al. Residual cardiovascular risk in individuals on lipid-lowering treatment: quantifying absolute and relative risk in the community. Open Heart 2018;5:e000722.
6. Bonner C, Bell K, Jansen J et al. Should heart age calculators be used alongside absolute cardiovascular disease risk assessment? BMC Cardiovasc Disord 2018;18:19.
7. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
8. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377:1119-31.
9. Varbo A, Nordestgaard BG. Remnant cholesterol and triglyceride-rich lipoproteins in atherosclerosis progression and cardiovascular disease. Arterioscler Thromb Vasc Biol 2016;36:2133-2135.
10. Budoff M, Muhlestein JB, Le VT et l. Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200–499 mg/dL) on statin therapy: Rationale and design of the EVAPORATE study. Clinical Cardiol 2018;41:13–19.
11. Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial. Clin Cardiol 2017;40:138–148.
12. Olkkonen VM, Sinisalo J, Jauhiainen M. New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk? Atherosclerosis 2018; doi: 10.1016/j.atherosclerosis.2018.03.019. [Epub ahead of print]